Nonmyeloablative haploidentical peripheral blood stem cell transplantation in congenital anemias

基于我们的小鼠数据，我们制定了一项1期和2期方案，采用阿仑单抗、400cGy全身照射（TBI）和移植后环磷酰胺（PT-Cy）剂量递增，队列1为0mg/kg，队列2为50mg/kg，队列3为100mg/kg。共有21例镰状细胞病患者和2例地中海贫血患者接受了移植，并出现了肝硬化、肺动脉高压、心力衰竭和终末期肾病等并发症。移植率从第一队列的1/3（33%）提高到第二队列的5/8(63%)，第三队列的10/12（83%）。在随后的队列中，供体骨髓和CD3嵌合的百分比也有所改善。总生存率为78.3%；3例在镰状细胞病复发后死亡，1例在第二次移植后死亡。移植后100天前无死亡病例。目前，第一队列中有0%，第二队列中有25%，第三队列中有50%的患者没有患病。没有2-4级急性或中重度慢性移植物抗宿主病（GVHD）。因此，我们已经证明PT-Cy可以改善早期死亡风险高的SCD患者的移植。当我们达到研究的停止规则时，我们开启了一个新的方案，增加了额外的免疫抑制，试图提高成功率，同时保持GVHD的低风险。自2017年6月以来，已有17例患者移植。16例患者获得高供体嵌合水平。1例有中风史和慢性血栓栓塞性肺动脉高压的抗凝患者在第二次移植后60天死亡。12例患者中有1例发展为2级急性GVHD，对类固醇反应良好。一名患者排斥他的移植物，需要输注他的备用自体细胞。由于新冠肺炎疫情的限制，我们今年最多只能移植4名患者，但希望能回到每年移植10名患者的目标。我们还将继续寻找与移植物排斥反应相关的早期生物标志物，试图在早期和可能更可逆的状态下识别移植物排斥反应，并探索移植物移植和耐受诱导的机制。我们还试图确定患者是否确实耐受他们的移植物，以便可以停止不必要的免疫抑制。最后，我们将继续监测移植的后期效应，包括移植对心脏、肺、肾脏的影响和髓系恶性肿瘤的发病率，并对接受治疗性治疗的镰状细胞病患者的心脏、肺、肾脏、大脑和神经认知功能进行深度表型分析。

Based on our murine data, we developed a phase 1 and 2 protocol employing alemtuzumab, 400cGy total body irradiation (TBI) and escalating doses of post-transplant cyclophosphamide (PT-Cy) ranging from 0mg/kg in cohort 1 and 50mg/kg in cohort 2 to 100mg/kg in cohort 3. A total of 21 patients with sickle cell disease and 2 patients with beta thalassemia were transplanted and had complications including cirrhosis, pulmonary hypertension, heart failure, and end-stage renal disease. The engraftment rate improved from 1/3 (33%) in the first cohort, to 5/8 (63%) in the second cohort to 10/12 (83%) in the third cohort. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. Overall survival is 78.3%; 3 died after return of their sickle cell disease and 1 following second transplant. There was no mortality before 100 days post-transplant. At present, 0% in the first cohort, 25% in the second cohort, and 50% in the third cohort remain free of their disease. There was no Grade 2-4 acute or moderate to severe chronic graft-versus-host disease (GVHD). Therefore, we have shown that PT-Cy improves engraftment in patients with SCD who are at high risk for early mortality. As we reached stopping rules for the study, we opened a new protocol which adds additional immunosuppression in an attempt to improve the success rate while maintaining a low risk of GVHD. Since June 2017, 17 patients have been transplanted. 16 patients achieved high donor chimerism levels. One patient with history of stroke and chronic thromboembolic pulmonary hypertension on anticoagulation died 60 days after her second transplant. One of the 12 developed Grade 2 acute GVHD which responded well to steroids. One patient rejected his graft and required infusion of his backup autologous cells. Due to COVID-19 restrictions, we will only transplant at most 4 patients this year, but hope to get back on track with our goal of transplanting 10 patients per year. We will also continue our search for early biomarkers associated with graft rejection in an attempt to identify graft rejection at an early and potentially more reversible state and explore mechanisms of engraftment and tolerance induction. We also seek to identify whether patients are indeed tolerant of their grafts so that unnecessary immunosuppression can be discontinued. Lastly, we will continue to monitor late effects of transplant including impact of transplant on the heart, lung, kidneys, and incidence of myeloid malignancies and perform deep phenotyping of the heart, lung, kidneys, brain, and neurocognitive function in patients with sickle cell disease who undergo curative therapies as compared to standard of care.